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?Np63? suppresses cells invasion by downregulating PKC?/Rac1 signaling through miR-320a.

ABSTRACT: ?Np63?, a member of the p53 family of transcription factors, is overexpressed in a number of cancers and plays a role in proliferation, differentiation, migration, and invasion. ?Np63? has been shown to regulate several microRNAs that are involved in development and cancer. We identified miRNA miR-320a as a positively regulated target of ?Np63?. Previous studies have shown that miR-320a is downregulated in colorectal cancer and targets the small GTPase Rac1, leading to a reduction in noncanonical WNT signaling and EMT, thereby inhibiting tumor metastasis and invasion. We showed that miR-320a is a direct target of ?Np63?. Knockdown of ?Np63? in HaCaT and A431 cells downregulates miR-320a levels and leads to a corresponding elevation in PKC? transcript and protein levels. Rac1 phosphorylation at Ser71 was increased in the absence of ?Np63?, whereas overexpression of ?Np63? reversed S71 phosphorylation of Rac1. Moreover, increased PKC? levels, Rac1 phosphorylation and cell invasion observed upon knockdown of ?Np63? was reversed by either overexpressing miR-320a mimic or Rac1 silencing. Finally, silencing PKC? or treatment with the PKC inhibitor Gö6976 reversed increased Rac1 phosphorylation and cell invasion observed upon silencing ?Np63?. Taken together, our data suggest that ?Np63? positively regulates miR-320a, thereby inhibiting PKC? expression, Rac1 phosphorylation, and cancer invasion.

SUBMITTER: Aljagthmi AA

PROVIDER: S-EPMC6742631 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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ΔNp63α suppresses cells invasion by downregulating PKCγ/Rac1 signaling through miR-320a.

Aljagthmi Amjad A AA Hill Natasha T NT Cooke Mariana M Kazanietz Marcelo G MG Abba Martín C MC Long Weiwen W Kadakia Madhavi P MP

Cell death & disease 20190912 9

ΔNp63α, a member of the p53 family of transcription factors, is overexpressed in a number of cancers and plays a role in proliferation, differentiation, migration, and invasion. ΔNp63α has been shown to regulate several microRNAs that are involved in development and cancer. We identified miRNA miR-320a as a positively regulated target of ΔNp63α. Previous studies have shown that miR-320a is downregulated in colorectal cancer and targets the small GTPase Rac1, leading to a reduction in noncanonica ...[more]

PMID: 31515469

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Project description:BackgroundMicroRNAs (miRNAs) serve as important regulators of the tumorigenesis and progression of many human cancers. Therefore, we evaluated the biological function and underlying mechanism of miR-363 in clear cell renal cell carcinoma (ccRCC).MethodsThe expression of miR-363 in ccRCC tissues compared with adjacent normal renal tissues was detected by quantitative real-time polymerase chain reaction, and the association between miR-363 levels and prognosis of ccRCC patients was analyzed. The candidate target gene of miR-363 was determined by in silico analysis and luciferase reporter assays. The effects of miR-363 on the proliferation, migration and invasion of ccRCC cells in vitro were determined by MTS assay, colony formation assay, Transwell assay and wound healing assay. We also investigated the roles of miR-363 in vivo by a xenograft tumour model. The mechanism of miR-363 on the proliferation, migration and invasion of ccRCC was determined by gain- and loss-of-function analyses.Resultswe demonstrated that miR-363 expression was obviously downregulated in ccRCC tissues and that reduced miR-363 expression was correlated with poor disease-free survival (DFS) in ccRCC patients after surgery. S1PR1 expression was inversely correlated with the level of miR-363 in human ccRCC samples. Luciferase reporter assays suggested that S1PR1 was a direct functional target of miR-363. miR-363 downregulated S1PR1 expression and suppressed the proliferation, migration and invasion abilities of ccRCC cells in vitro and suppressed xenograft tumour growth in vivo. Importantly, miR-363 exerted its biological function by inhibiting S1PR1 expression in ccRCC cells, leading to the repression of ERK activation. Moreover, we found that the levels of downstream effectors of ERK, including PDGF-A, PDGF-B, and epithelial-mesenchymal transition (EMT)-related genes, were decreased after miR-363 overexpression.ConclusionsOur results suggest that miR-363 acts as a tumour suppressor by directly targeting S1PR1 in ccRCC and may be a potential new therapeutic target for ccRCC.

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?Np63? suppresses cells invasion by downregulating PKC?/Rac1 signaling through miR-320a.

Publications

ΔNp63α suppresses cells invasion by downregulating PKCγ/Rac1 signaling through miR-320a.

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